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Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity
Open accessAbstract
By integrating an agonist satiety signal, provided by alpha-melanocyte-stimulating hormone (alpha-MSH), and an antagonist signal, provided by agouti-related protein (AGRP), the melanocortin-4 receptor (MC4-R) is a key element in the hypothalamic control of food intake. Inactivation of the gene encoding this G protein-coupled receptor causes obesity in mice. In humans, frameshift mutations in MC4-R cause an early-onset dominant form of obesity in two families. In this study we find a high frequency (4%) of rare heterozygous MC4-R mutations in a large population of morbidly obese patients. No such mutations were found in controls. By analyzing the phenotypes of the probands carrying these mutations, we demonstrate that these patients display a common, nonsyndromic form of obesity. Interestingly, functional analysis of the mutant receptors indicates that obesity-associated defects in MC4-R range from loss of function to constitutive activation. Transmission of these mutations in the families of the carriers indicates a variable expressivity that is not related to the functional severity of the mutations. This variable expressivity of MC4-R-associated obesity is not due to variations in genes for alpha-MSH or AGRP. Taken together, these results demonstrate that MC4-R mutations are a frequent but heterogeneous genetic cause of morbid obesity.
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“Disruption of POMC-MC4R signalling causes hyperphagia and is the most common known genetic cause of morbid obesity in children193,194.”
From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [194]
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(2000) · PubMed · Cited by 13,173
Obesity : Preventing and managing the global epidemic
Akram, D. S., Astrup, A. V., Atinmo, T., Boissin, J.-L., Bray, G. A., Carroll, K. N., Chitson, P., Chen, C., Dietz, W. H., Hill, J. O., et al. (2000) · Research at the University of Copenhagen (University of Copenhagen) · Cited by 12,945
The Disease Burden Associated With Overweight and Obesity
Must, A. (1999) · JAMA · doi:10.1001/jama.282.16.1523 · Cited by 4,827
The three-factor eating questionnaire to measure dietary restraint, disinhibition and hunger
Stunkard, A. J., & Messick, S. (1985) · Journal of Psychosomatic Research · doi:10.1016/0022-3999(85)90010-8 · Cited by 4,687
A short questionnaire for the measurement of habitual physical activity in epidemiological studies
Baecke, J. A. H., BUREMA, J., & Frijters, J. E. R. (1982) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/36.5.936 · Cited by 3,950
Targeted disruption of the melanocortin-4 receptor results in obesity in mice
Huszar, D., Lynch, C. A., Fairchild-Huntress, V., Dunmore, J. H., Fang, Q., Berkemeier, L. R., Gu, W., Kesterson, R. A., Boston, B. A., Cone, R. D., et al. (1997) · Cell · doi:10.1016/s0092-8674(00)81865-6 · Cited by 3,030
Congenital leptin deficiency is associated with severe early-onset obesity in humans
Montague, C. T., Farooqi, I. S., Whitehead, J. P., Soos, M. A., Rau, H., Wareham, N. J., Sewter, C. P., Digby, J. E., Mohammed, S. N., Hurst, J. A., et al. (1997) · Nature · doi:10.1038/43185 · Cited by 2,936
The Spread of the Obesity Epidemic in the United States, 1991-1998
Mokdad, A. H. (1999) · JAMA · doi:10.1001/jama.282.16.1519 · Cited by 2,384
A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction
Clément, K., Vaisse, C., Lahlou, N., Cabrol, S., Pelloux, V., Cassuto, D., Gourmelen, M., Dina, C., Chambaz, J., Lacorte, J.-M., et al. (1998) · Nature · doi:10.1038/32911 · Cited by 2,346
Self-citationEnvironmental Contributions to the Obesity Epidemic
Hill, J. O., & Peters, J. C. (1998) · Science · doi:10.1126/science.280.5368.1371 · Cited by 2,258
Role of melanocortinergic neurons in feeding and the agouti obesity syndrome
Fan, W., Boston, B. A., Kesterson, R. A., Hruby, V. J., & Cone, R. D. (1997) · Nature · doi:10.1038/385165a0 · Cited by 1,924
Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein
Ollmann, M. M., Wilson, B. D., Yang, Y.-K., Kerns, J. A., Chen, Y., Gantz, I., & Barsh, G. S. (1997) · Science · doi:10.1126/science.278.5335.135 · Cited by 1,881
Annual Deaths Attributable to Obesity in the United States
Allison, D. B. (1999) · JAMA · doi:10.1001/jama.282.16.1530 · Cited by 1,863
Krude, H., Biebermann, H., Luck, W., Horn, R., Brabant, G. E., & Grüters, A. (1998) · Nature Genetics · doi:10.1038/509 · Cited by 1,769
Differential signal transduction by five splice variants of the PACAP receptor
Spengler, D., Waeber, C., Pantaloni, C., Holsboer, F., Bockaert, J., Seeburg, P. H., & Journot, L. (1993) · Nature · doi:10.1038/365170a0 · Cited by 1,182
A frameshift mutation in MC4R associated with dominantly inherited human obesity
Yeo, G. S. H., Farooqi, I. S., Aminian, S., Halsall, D. J., Stanhope, R. G., & O'Rahilly, S. (1998) · Nature Genetics · doi:10.1038/2404 · Cited by 1,159
A leptin missense mutation associated with hypogonadism and morbid obesity
Strobel, A., Issad, T., Camoin, L., Ozata, M., & Strosberg, A. D. (1998) · Nature Genetics · doi:10.1038/ng0398-213 · Cited by 1,158
Jackson, R. S., Creemers, J. W. M., Ohagi, S., Raffin-Sanson, M.-L., Sanders, L., Montague, C. T., Hutton, J. C., & O'Rahilly, S. (1997) · Nature Genetics · doi:10.1038/ng0797-303 · Cited by 1,153
Body Mass Index variations: centiles from birth to 87 years.
Rolland‐Cachera, M., Cole, T. J., Sempe, M., Tichet, J., Rossignol, C., & Charraud, A.-M. (1991) · PubMed · Cited by 1,127
A frameshift mutation in human MC4R is associated with a dominant form of obesity
Vaisse, C., Clément, K., Guy-grand, B., & Froguel, P. (1998) · Nature Genetics · doi:10.1038/2407 · Cited by 1,091
Self-citationThe spread of the obesity epidemic in the United States
Mokdad, A. H., Serdula, M. K., & Dietz, W. H. (1999) · Cited by 985
Molecular cloning, expression, and gene localization of a fourth melanocortin receptor
Gantz, I., Miwa, H., Konda, Y., Shimoto, Y., Tashiro, T., Watson, S. J., DelValle, J., & Yamada, T. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)82452-8 · Cited by 846
The Search for Human Obesity Genes
Comuzzie, A. G., & Allison, D. B. (1998) · Science · doi:10.1126/science.280.5368.1374 · Cited by 543
Hinney, A., Schmidt, A., Nottebom, K., Heibült, O., Becker, I., Ziegler, A., Gerber, G., Sina, M., Görg, T., Mayer, H. G., et al. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.4.5728 · Cited by 462
Overexpression of Agrt leads to obesity in transgenic mice
Graham, M., Shutter, J. R., Sarmiento, U. M., Sarosi, L., & Stark, K. L. (1997) · Nature Genetics · doi:10.1038/ng1197-273 · Cited by 387
Herçberg, S., Preziosi, P., Briançon, S., Galan, P., Triol, I., Malvy, D. J.-M., Roussel, A., & Favier, A. E. (1998) · Controlled Clinical Trials · doi:10.1016/s0197-2456(98)00015-4 · Cited by 371
A genome-wide scan for human obesity genes reveals a major susceptibility locus on chromosome 10
Hager, J., Christian Dina, C., Francke, S., Dubois, S. G., Barat‐Houari, M., Vatin, V., Vaillant, E., Lorentz, N., Basdevant, A., Clément, K., et al. (1998) · Nature Genetics · doi:10.1038/3123 · Cited by 369
Self-citationRouillé, Y., Duguay, S. J., Lund, K., Furuta, M., Gong, Q., Lipkind, G. M., Oliva, A. A., Chan, S. J., & Steiner, D. F. (1995) · Frontiers in Neuroendocrinology · doi:10.1006/frne.1995.1012 · Cited by 347
The rapid detection of unknown mutations in nucleic acids
Grompe, M. (1993) · Nature Genetics · doi:10.1038/ng1093-111 · Cited by 311
Identification and functional analysis of novel human melanocortin-4 receptor variants.
Gu, W., Tu, Z., Kleyn, P. W., Kissebah, A. H., Duprat, L. J., Lee, J., Chin, W., Maruti, S., Deng, N., Fisher, S. L., et al. (1999) · Diabetes · doi:10.2337/diabetes.48.3.635 · Cited by 191
A Ligand-Mimetic Model for Constitutive Activation of the Melanocortin-1 Receptor
Lu, D., Våge, D. I., & Cone, R. D. (1998) · Molecular Endocrinology · doi:10.1210/mend.12.4.0091 · Cited by 84
Gotoda, T., Scott, J., & Aitman, T. J. (1997) · Diabetologia · doi:10.1007/s001250050777 · Cited by 83
Human Placental Protein 14 Gene: Sequence and Characterization of a Short Duplication
Vaisse, C., Atger, M., POTIER, B., & Milgröm, E. (1990) · DNA and Cell Biology · doi:10.1089/dna.1990.9.401 · Cited by 72
Self-citationG Proteins, Receptors, and Disease
Spiegel, A. M. (1998) · Humana Press eBooks · doi:10.1007/978-1-4612-1802-9 · Cited by 69
Association of poorly controlled diabetes with low serum leptin in morbid obesity
Clément, K., Lahlou, N., Ruiz, J., Hager, J., Bougneres, P. F., Basdevant, A., Guy-grand, B., & Froguel, P. (1997) · International Journal of Obesity · doi:10.1038/sj.ijo.0800440 · Cited by 58
Self-citationDeletions of the N‐terminal regions of the human melanocortin receptors
Schiöth, H. B., Petersson, S., Muceniece, R., Szardenings, M., & Wikberg, J. E. S. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)00593-0 · Cited by 53
Haplosufficiency of the melanocortin-4 receptor gene in individuals with deletions of 18q
Cody, J. D., Reveles, X. T., Hale, D. E., Lehman, D. M., Coon, H. H., & Leach, R. J. (1999) · Human Genetics · doi:10.1007/s004390051125 · Cited by 32
Delobel, B., Vasseur-Delannoy, V., Pini, G., Zapella, M., Tardieu, M., Vallée, L., & CROQUETTE, M. F. (1998) · PubMed · Cited by 26
Sundaramurthy, D., Campbell, D. A., Leek, J. P., Markham, A. F., & Pieri, L. F. (1998) · Cytogenetic and Genome Research · doi:10.1159/000015074 · Cited by 19
Nordenskj�ld, A., Magnus, �., Aagen�s, �., & Knudtzon, J. (1998) · American Journal of Medical Genetics · doi:10.1002/(sici)1096-8628(19981116)80:3 · Cited by 19
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- Rolland-Cachera, 1991, Eur J Clin Nutr, 45, 13
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Genome-wide association studies for common diseases and complex traits
Hirschhorn, J. N., & Daly, M. J. (2005) · Nature Reviews Genetics · doi:10.1038/nrg1521 · Cited by 2,923
Clinical Spectrum of Obesity and Mutations in the Melanocortin 4 Receptor Gene
Farooqi, I. S., Keogh, J. M., Yeo, G. S. H., Lank, E. J., Cheetham, T., & O'Rahilly, S. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa022050 · Cited by 1,778
Anatomy and regulation of the central melanocortin system
Cone, R. D. (2005) · Nature Neuroscience · doi:10.1038/nn1455 · Cited by 1,583
Hampl, S. E., Hassink, S. G., Skinner, A. C., Armstrong, S. C., Barlow, S. E., Bolling, C. F., Avila Edwards, K. C., Eneli, I., Hamre, R., Joseph, M. M., et al. (2023) · Pediatrics · doi:10.1542/peds.2022-060640 · Cited by 1,389
Obesity-Induced Hypertension: Interaction of Neurohumoral and Renal Mechanisms
Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z., & Hall, M. E. (2015) · Circulation Research · doi:10.1161/circresaha.116.305697 · Cited by 1,360
Metadata
- Authors
- Vaisse, C., Clement, K., Durand, E., Hercberg, S., Guy-Grand, B., & Froguel, P.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Hôtel-Dieu de Paris (FR)
- University of California, San Francisco (US)
- Corresponding author
- Vaisse, Christian
- Venue
- Journal of Clinical Investigation
- Published
- 2000-07-15
- Volume
- 106
- Issue
- 2
- Pages
- 253-262
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC314306
- OpenAlex
- W2118192748
- Cited by
- 897
- References
- 40
- Citations by year
- 2026: 11 · 2025: 17 · 2024: 21 · 2023: 26 · 2022: 18 · 2021: 32 · 2020: 27 · 2019: 28 · 2018: 27 · 2017: 22 · 2016: 26 · 2015: 34 · 2014: 36 · 2013: 22 · 2012: 28
- FWCI
- 20.59
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Danone
- Instituto Danone
- Servier
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Social Sciences › Psychology › Clinical Psychology › Eating Disorders and Behaviors
- Keywords
- melanocortin-4 receptor, MC4R mutations, morbid obesity, agouti-related protein, alpha-melanocyte-stimulating hormone, G protein-coupled receptors, loss of function, constitutive receptor activation, variable expressivity, genetic heterogeneity
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, alpha-MSH, Child, Eating, Female, Genetic Testing, Heterozygote, Humans, Male, Middle Aged, Mutation, Obesity, Morbid, Pedigree, Proteins, Cohort Studies, Frameshift Mutation, Receptors, Corticotropin, Penetrance, Mutation, Missense, Intercellular Signaling Peptides and Proteins, Receptor, Melanocortin, Type 4, Agouti-Related Protein
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